Aminobenzoic acid derivatives

ABSTRACT

To provide a compound which exhibits a serotonin antagonism and an acetylcholine release accelerating activity at a well-balanced activity ratio. An aminobenzoic acid derivative represented by the general formula (I) or (II) or a pharmacologically acceptable salt thereof: ##STR1##  wherein R 1  represents a group represented by the formula: ##STR2## {wherein A represents a group represented by formula --CH 2  --X--CH 2  -- (wherein X represents O, &gt;N--R 6  or &gt;CHR 7  (wherein R 6  represents lower alkyl and R 7  represents hydrogen or lower alkoxy)), etc.; D and E each represents a group represented by formula --(CH 2 ) 3  --, etc., and R 2  represents lower alkyl. etc.}; R 9  represents alkynyl; R 10  represents amino, etc.; R 11  represents halogen; R 12  and R 13  each represent lower alkyl; a is an integer of 1 to 5; and b is an integer of 0 to 5!.

FIELD OF INDUSTRIAL APPLICATION

The present invention relates to an aminobenzoic acid derivative. Moreparticularly, it relates to an aminobenzoic acid derivative useful asdrugs.

BACKGROUND OF THE INVENTION AND PRIOR ART

The proportion of patients with indefinite complaints such as abdominaldistension, heartburn, nausea and vomiting among those withgastrointestinal diseases has recently increased steadily and nowreaches 60% or above.

Most of these indefinite complaints are caused by the functional anomalyof the digestive tract. For example, it is known that a patient withepigastric indefinite complaints such as chronic gastritis is in a stateof delayed gastric emptying, while a patient with hypogastric indefinitecomplaints such as irritable bowel syndrome including abnormalevacuation and abdominal pain as the cardinal symptom is in a state ofintestinal hyperanakinezia.

It is ascertained that stress and anxiety are causative of anyindefinite complaint, and in this sence, it is not too much to say thatindefinite complaint is one of modern diseases.

Dopamine antagonists, musculotropic agents for regulating the movementof smooth muscles and acetylcholine release accelerators are now used inorder to ameliorate the above gastrointestinal indefinite complaints.However, dopamine antagonists cause potent adverse reactions such asparkinsonism, so that they must be used carefully; musculotropic agentsfor regulating the movement of smooth muscles cause adverse reactionssuch as constipation unfavorably; and acetylcholine release acceleratorsdo not effectively act as an antiemetic or anxiolytic, thus beingunsatisfactory.

SUMMARY OF THE INVENTION

Under these circumstances, the inventors of the present invention haveset about making studies for the purpose of developing a drug which isefficacious in treating all types of patients with gastrointestinalindefinite complaints without causing any potent adverse reaction andexhibits a depressant activity against anxiety which is nearly alwaysfound as one of the background factors of such patients.

As a result of the studies, it has been concluded that the aboverequirements can be fulfilled by a drug exhibiting both a serotonin(hereinafter abbreviated to "5-HT₃ ") antagonism and an acetylcholine(hereinafter abbreviated to "ACh") release accelerating activity.Therefore, further studies have been made in order to find a compoundexhibiting both the activities at a well-balanced activity ratio to findout that the object can be attained by using an aminobenzoic acidderivative represented by the following general formula (I) or (II) or apharmacologically acceptable salt thereof. The present invention hasbeen accomplished on the basis of this finding.

Although aminobenzoic acid derivatives useful as drugs have beendescribed in JP-B No. 29356/1986 and JP-A Nos. 36675/1984, 72886/1985,226858/1985, 152628/1986, 161282/1986, 155277/1987 and 313757/1988, thecompounds of the present invention are different from them in thechemical structures.

The compound of the present invention is an aminobenzoic acid derivativerepresented by the following general formula (I) or a pharmacologicallyacceptable salt thereof: ##STR3## wherein R¹ represents a grouprepresented by the formula: ##STR4## {wherein A and B may be the same ordifferent from each other and each represents a group represented byformula --CH₂ --X--CH₂ -- (wherein X represents O, >N--R⁶ or >CHR⁷(wherein R⁶ represents lower alkyl; and R⁷ represents hydrogen or loweralkoxy) or a group represented by the formula: ##STR5## (wherein R⁸represents hydrogen, hydroxyl or lower alkoxy); D and E may be the sameor different from each other and each represents a group represented byformula --(CH₂)₃ -- or a group represented by formula --O--(CH₂)₂ --; R²represents hydrogen, lower alkyl or arylalkyl, provided that when R⁸ ishydrogen, R² is not methyl; and R³ represents hydrogen, lower alkyl, agroup represented by formula --CO₂ (CH₂)_(n) H (wherein n is an integerof 1 to 4) or a group represented by the formula: ##STR6## (wherein m isan integer of 1 to 4; X represents halogen, lower alkyl or lower alkoxy;and p is zero or an integer of 1 to 5)};

R⁹ represents alkynyl;

R¹⁰ represents amino, acylamino or alkylamino; and

R¹¹ represents halogen!.

The invention provides a pharmacological composition comprising apharmacologically effective amount of the compound as defined above or apharmacologically acceptable salt thereof and a pharmacologicallyacceptable carrier.

The invention moreover provides a method for preventing ortherapeutically treating a disease against which serotonin antagoism oran acetylcholine release accelerating action is efficacious byadministering a pharmacologically effective amount of the compound to asubject who suffers or will suffer from the disease.

Further, the compound of the present invention is also an aminobenzoicacid derivative represented by the following general formula (II) or apharmacologically acceptable salt thereof: ##STR7## (wherein R¹⁰represents amino, acylamino or alkylamino; R¹¹ represents halogen; R¹²and R¹³ each represent lower alkyl; a is an integer of 1 to 5,preferably 2; and b is an integer of 0 to 5, preferably 0).

In the general formulae (I) and (II), the lower alkyl defined withrespect to R², R³, R⁶, R¹² and R¹³ is a linear or branched one having 1to 3 carbon atoms, such as methyl, ethyl, propyl or isopropyl. Further,the lower alkoxy defined with respect to R⁷ and R⁸ is methoxy, ethoxy,n-propoxy or isopropoxy. Furthermore, the arylalkyl defined with respectto R² is benzyl, phenylethyl, phenylpropyl or the like.

The alkynyl defined with respect to R⁹ is preferably ##STR8##

The acyl constituting the acylamino defined with respect to R¹⁰ may beone derived from an aliphatic saturated carboxylic acid, an aliphaticunsaturated carboxylic acid, a saturated or unsaturated carbocycliccarboxylic acid, a heterocyclic carboxylic acid, a hydroxycarboxylicacid or any other carboxylic acid. Examples of the acyl include formyl,acetyl, propionyl, benzoyl, toluoyl, naphthoyl, furoyl and nicotinoyl.

Further, the alkyl constituting the alkylamino defined with respect toR¹⁰ is as defined above with respect to the lower alkyl.

The halogen defined with respect to R¹¹ is chlorine, fluorine, bromineor the like.

The pharmacologically acceptable salt according to the present inventionincludes inorganic acid salts such as hydrochloride, hydrobromide,sulfate and phosphate; organic acid salts such as acetate, maleate,tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate; andamino acid salts such as aspartate and glutamate.

Further, the compounds according to the present invention may be presentas hydrates and the present invention includes these hydrates.

Although the compound of the present invention may be present asgeometrical isomers or optical isomers, it is needless to say that thepresent invention includes all of the isomers. Further, the compound ofthe present invention may be any of S-, R- and RS-forms.

The compound according to the present invention exhibits a serotoninantagonism and an acetylcholine release accelerating activity and istherefore useful as a preventive and therapeutic agent for diseasesagainst which these activities are efficacious. Further, the compoundaccording to the present invention is useful also as an agent forincreasing a gastrointestinal function, such as one for increasing agastric emptying function, an antiemetic or an anxiolytic and as apreventive and therapeutic agent for irritable bowel syndrome.

In this specification, the term "serotonin antagonism" refers to 5-HT₃antagonism. More precisely, the compound of the present inventionselectively inhibits S-HT₃ among serotonin antagonists. Further, theacetylcholine release accelerating action is guessed to be due to thefunction of 5-HT₄ as an agonist.

Among the compounds according to the present invention, thoserepresented by the following structural formulae and pharmacologicallyacceptable salts thereof are preferable: ##STR9## In particular, acompound represented by formula ##STR10## and pharmacologicallyacceptable salts thereof are still preferable.

Representative processes for preparing the compound of the presentinvention will now be described.

Preparation process 1

A compound represented by the general formula (I) wherein R¹⁰ is aminocan be prepared by the following process: ##STR11## (wherein R⁹ and R¹¹are each as defined above; Q represents lower alkyl; Z representshalogen; and Ac represents acetyl)

In this step, a compound represented by the general formula (V) isprepared by reacting a compound represented by the general formula (IV)with a compound represented by the general formula (VI) or (VII).

In reacting the compound (IV) with the compound (VI),N,N-dimethylformamide, dimethyl sulfoxide or the like is preferably usedas the solvent.

It is preferred that the reaction temperature range from 0° to 100° C.,and the reaction time range from 30 minutes to 3 hours.

The reaction of the compound (IV) with the compound (VII) is conductedby reacting triphenylphosphine with an azodicarboxylate either in asolvent such as tetrahydrofuran or benzene or in the absence of anysolvent in an inert gas atmosphere preferably at a temperature of -80°to 0° C., adding a solution of the compound (VII) in tetrahydrofuran anda solution of the compound (IV) therein to the obtained reaction mixturesuccessively, and reacting the resulting mixture for 30 minutes toseveral hours while bringing the temperature to room temperature, thusgiving a compound (V). ##STR12## (wherein R⁹, R¹¹, Q and Ac are each asdefined above).

In this step, the compound (V) prepared in Step 1 is deacetylated. It ispreferable that sulfuric acid be used in an equivalent amount or excess.

The solvent to be used in the reaction is particularly preferably analcoholic solvent such as methanol or ethanol.

The reaction temperature preferably ranges from about 0° to 50° C.##STR13## (wherein R⁹, R¹¹ and Q are each as defined above)

In this step, the compound (VIII) prepared in Step 2 is hydrolyzed.

The hydrolysis is conducted in the presence of two or more equivalentsof a strong base such as sodium hydroxide or potassium hydroxide in analcoholic solvent such as methanol or ethanol at room temperature to100° C. for several hours, by which a compound (IX) is obtained.##STR14## (wherein R¹, R⁹ and R¹¹ are each as defined above).

In this step, a compound (I') is prepared by condensing the compound(IX) prepared in Step 3 with an amine (X) having an R¹ moiety.

The amine (X) can be prepared by, e.g., the process disclosed in JP-ANo. 202890/1990, 18885/1988 or 30785/1987 or EP-A 0469449. Thecondensation is conducted in the presence of a suitable dehydratingagent, for example, a carbodiimide such as dicyclohexylcarbodiimide.Alternatively, it may be conducted by converting the compound (IX) intoa conventional reactive derivative thereof such as an acid anhydride, amixed acid anhydride, an acid azide, an active ester thereof withN-hydroxybenzotriazole, N-hydroxysuccinimide or the like, or acidchloride, and reacting the derivative with the amine (X). When thecondensation is conducted through a mixed acid anhydride, the mixed acidanhydride may be one prepared by the use of a chlorocarbonic acid estersuch as methyl chlorocarbonate, ethyl chlorocarbonate or phenylchlorocarbonate.

These reactions may be conducted either in the absence of any solvent orin the presence of a solvent inert to the reactions, e.g., benzene,toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride,N,N-dimethylformamide or pyridine.

When the reaction is conducted in a solvent, the simultaneous use of aninorganic base such as sodium hydrogencarbonate, potassium carbonate,sodium carbonate or sodium hydroxide or an organic base such astriethylamine or pyridine gives more desirable results.

Preparation process 2

A compound represented by the general formula (I) wherein R¹⁰ is aminocan be prepared also by the following process: ##STR15## (wherein R⁹,R¹¹, Z and Ac are each as defined above).

In this step, a compound represented by the general formula (XIII) isprepared by reacting a compound represented by the general formula (XII)with a compound represented by the general formula (VI) in the presenceof a base for several hours.

The base is preferably potassium carbonate or sodium carbonate, thoughany base is usable in this step.

The solvent to be used in the reaction may be any one inert to thereaction.

The reaction temperature preferably ranges from about 0° to 100° C.##STR16## (wherein R⁹, R¹¹ and Ac are each as defined above)

In this step, the compound (XIII) prepared in Step 1 was deacetylatedinto a compound represented by the general formula (XIV).

The deacetylation is conducted in the conventional manner, e.g., bytreating the compound (XIII) in a mixture comprising sulfuric acid in anequivalent amount or excess and a solvent such as methanol or ethanolfor several hours.

The reaction temperature preferably ranges from about 0° to 50° C.##STR17## (wherein R⁹ and R¹¹ are each as defined above).

In this step, the compound (XIV) prepared in Step 2 is hydrolyzed.

This hydrolysis is conducted in the conventional manner, for example, bytreating the compound (XIV) in an alcoholic solvent such as methanol orethanol in the presence of two or more equivalents of a strong base suchas sodium hydroxide or potassium hydroxide at a temperature ranging fromroom temperature to 100° C. for several hours. ##STR18## (wherein R¹, R⁹and R¹¹ are each as defined above)

In this step, the objective compound (I') is prepared in the same manneras that of Step 4 of Preparation process 1.

A compound represented by the general formula (I) wherein R¹⁰ is a groupother than amino can be prepared by, for example, a process whichcomprises converting the amino group of the compound (VIII) into anacylamino or alkylamino group through acylation or alkylation,hydrolyzing the resulting compound, and condensing the hydrolysate witha tropane or a tropine.

Experimental Examples will now be described to illustrate the effects ofthe compounds according to the present invention in detail.

Experimental Example 1

Antagonism against 2-methylserotonin-induced contraction of ileum(serotonin 3 antagonism)

This experiment was made according to the method of Sanger et al. seeEur. J. Pharmacol., 159, 118-124 (1989)!. The nonterminal ileum of aHartley male guinea pig was suspended in the Krebs solution (37° C.) byapplying a load of 0.5 g, and a gaseous mixture comprising 95% of oxygenand 5% of carbon dioxide was passed through the solution. Thecontraction of the ileum was isometrically determined. After allowingthe ileum to stand for one or more hours for stabilization, a solutionof a test compound was added to the solution, and after 30 minutes,2-methylscrotonin was noncumulatively added. The pA2 value wascalculated from the rightward shift of the dose-response curve of the2-methylserotonin-induced contraction caused by the test compoundaccording to the method of Rossum et al. see Arch. Int. Pharmacodyn.142, 299(1963)!. BRL 24924 (Renzapride) was used as a control in thisexperiment.

The structural formula of BRL 24924 is as follows: ##STR19##

The results are given in Table 1.

                  TABLE 1    ______________________________________           Test compd.           (Ex. compd.)                    pA2    ______________________________________            6       7.7           20       7.2           fraction 1           20       7.9           fraction 2           31       7.2           fraction 1           31       8.3           fraction 2           53       8.6           fraction 2-1           53       7.9           fraction 2-2           BRL 24924                    6.6           (Renzapride)    ______________________________________

Experimental Example 2

Activity against cisplatin-induced vomiting of beagle

Beagles weighing 7 to 12 kg were used. 3 mg/kg of cisplatin (a productof Sigma) (1 ml/kg of physiological saline) was administered to eachbeagle through the vein of one of its forefeet. One hour after theadministration, physiological saline (0.2 ml/kg) was administered to acontrol group of beagles and a solution of a test compound inphysiological saline was administered to a test group of beagles, eachthrough the vein of the other forefoot. The frequency of vomitingobserved over a 5-hour period from the administration of cisplatin wasrecorded and the inhibitory ratio of the test compound was calculatedaccording to the following formula.

The results are given in Table 2. ##EQU1##

                  TABLE 2    ______________________________________                  Inhibitory ratio against    Test compd.   cisplatin-induced vomiting (%)    (Ex. compd.)  0.03 mg/kg  0.1 mg/kg    ______________________________________     2            14          53     6                        77    20                        22    fraction 1    20            14          24    fraction 2    31            63          92    fraction 2    BRL 24924     19          61    (Renzapride)    ______________________________________

Experimental Example 3

Activity for increasing gastric emptying function

This experiment was made according to the method of Decktot et al. seeEur. J. Pharmacol., 147, 313-316 (1988)!. Fischer male rats (weight: 160to 180 g) were fasted for 18 hours before 3 ml of a test food comprisingmethylcellulose, beef bouillon, casein, sugar and corn starch was orallyadministered to each rat. One hour after the administration, the stomachwas extirpated from each rat. The gastric emptying ratio was calculatedfrom the weight of the test food remaining in the stomach. Thepercentage increment of the gastric emptying function was determined bycomparing the gastric emptying ratio of a medicated rat with that of acontrol rat. Each test compound (5 ml/kg) was orally administered onehour before the administration of the test food. BRL 24924 was used as acontrol in this experiment.

The results are given in Table 3.

                  TABLE 3    ______________________________________            Percentage increment of gastric            emptying function (%)    Test compd.              0.01     0.03    0.1    0.3   1    (Ex. compd.)              mg/kg    mg/kg   mg/kg  mg/kg mg/kg    ______________________________________     2        20.5*    19.7    19.8   30.6    15                         24.6*  30.6    20        3.9      8.9     22.9*  11.5    fraction 1    20                 14.0    23.3*  21.8    fraction 2    31                 0.8     0.8    14.1*    fraction 1    31        4.5      24.6*   25.8   33.2    fraction 2    53                         14.4*  16.1    fraction 2    53        14.4     22.2*   26.7   29.0    fraction 2-1    53                 6.6     21.3*  28.8    fraction 2-2    BRL 24924                  1.9    6.5   18.5*    (Renzapride)    ______________________________________     *minimum effective dose

Experimental Example 4

Effect of relaxing the contraction of muscular layer of esophagealmucosa of rat by stimulation with carbachol (activity of serotonin 4 asagonist)

This experiment was made according to the method of Baxter et al. seeNaunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991)!. Theesophagus of a rat was extirpated and freed from the outer tunicapropria to obtain the muscular layer of mucosa. This sample wassuspended in the Krebs-Henseleit solution kept at 37° C., while agaseous mixture comprising 95% of O₂ and 5% of CO₂ was passed throughthe solution. A load of 0.5 g was applied to each sample and thereaction was recorded isometrically. 1 μM of carbachol was added to eachsample to cause contraction, followed by the cumulative addition theretoof a solution of a test compound. The effect of the test compound wasdetermined as the ratio (%) of relaxation based on the maximumcontraction caused by carbachol. Table 4 shows the concentrations oftest compounds at which the maximum contraction caused by carbachol isrelaxed by 50%.

                  TABLE 4    ______________________________________                 Effect of relaxing the                 muscular layer of    Test compd.  esophageal mucosa of rat    (Ex. compd.) EC.sub.50 (μM)    ______________________________________     2           0.082     4           1.3     6           0.11    15           0.035    35           2.0    42           6.2    44           0.11    50           >10    19           >10    20           0.060    fraction 1    20           0.033    fraction 2    28           >10    fraction 1    28           >10    fraction 2    29           >10    31           0.044    fraction 1    31           0.19    fraction 2    53           0.31    fraction 2    53           0.30     fraction 2-1    53           0.18     fraction 2-2    55           0.64    BRL 24924    0.30    (Renzapride)    ______________________________________

It can be understood From the results of the above pharmacologicalexperiments that the compound of the present invention has a 5-HT₃antagonism and an ACh release accelerating activity and is thereforeeffective in increasing the gastrointestinal functions such as gastricemptying function and useful as an antiemetic.

It has been ascertained by recent studies that an ACh releaseaccelerating action is due to the action of 5-HT₄ as an agonist.Therefore, it is guessed that the increase of a gastrointestinalfunction by the compound according to the present invention may beinfluenced by such mechanism variously.

Accordingly, the compound of the present invention acts as a 5-HT₃antagonist and an ACh release accelerator and hence is useful as a drugbased on these activities.

The compound of the present invention is efficacious in the preventionand treatment of various diseases and specific examples of the diseasesinclude irritable bowel syndrome; reflux esophagitis; gastrointestinalsymptoms (such as heartburn, anorexia, nausea, vomiting, abdominal painand abdominal distension) caused by chromic gastritis, gastroptosis,postgastrectomy syndrome or the like; gastrointestinal symptoms andgastrointestinal insufficiency represented by those caused by theadministration of an anticancer drug or irradiation with radiation;anxiety; migraine; amenestic syndrome; senile dementia; Alzheimerdisease; and dependence. In particular, the compound of the presentinvention is excellent in the balance between 5-HT₃ antagonism and AChrelease accelerating activity, so that it is extremely efficaciousagainst gastrointestinal symptoms and gastrointestinal insufficiency.

Further, the compound of the present invention is less toxic and highlysafe, thus being valuable also in this sense.

The compound of the present invention is administered as a therapeuticand preventive agent for the above diseases in the form of tablet,powder, granule, capsule, syrup or inhalant. Although the dose thereofremarkably varies depending upon the extent of symptom, age, and thekind of disease, the dose per adult a day is generally about 0.01 to1000 mg, preferably 0.1 to 500 mg. still preferably 0.1 to 100 mg, whichis administered in one to several portions a day.

When the compound of the present invention is administered as aninjection. The dose is generally 1 to 3000 μg/kg, preferably about 3 to1000 μg/kg.

The pharmaceutical preparations according to the present invention areprepared by the use of the conventional carriers in the conventionalmanner.

More precisely, a solid preparation for oral administration according tothe present invention is prepared by adding a filler and, if necessary,a binder, disintegrator, lubricant, color and/or corrigent to an activeingredient and shaping the obtained mixture into a tablet, coatedtablet. granule, powder or capsule.

Examples of the filler include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide; those of the binderinclude polyvinyl alcohol, polyvinyl ether, ethylcellulose,methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin; those of the lubricant include magnesium stearate,talc, polyethylene glycol, silica and hardened vegetable oil; those ofthe color include those authorized as pharmaceutical additives; andthose of the corrigent include cocoa powder, menthol, aromatic powder,mentha oil, borneol and powdered cinnamon bark. Of course, the tabletand granule may be suitably coated with sugar, gelatin or the like, ifnecessary.

An injection according to the present invention is prepared by adding apit regulator, buffer, stabilizer and/or solubilizing agent to an activeingredient at need and formulating the mixture into an injection forsubcutaneous, intramuscular or intravenous administration by theconventional technique.

EXAMPLE

Examples according to the present invention will now be described,though it is needless to say that the present invention is not limitedto them.

Example 1

(S)-N-(9-Methyl-3-oxa-9-azabicyclo3.3.1!non-7α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide##STR20##

Ethyl chloroformate (0.54 g) was dropped into 30 ml of a dichloromethanesolution of 1.0 g of(S)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzoic acid and 0.8 g oftriethylamine under cooling with ice. The obtained mixture was stirredat room temperature for 10 minutes, followed by the addition thereto of1.37 g of 3α-amino-9-methyl-3-oxa-9-azabicyclo 3.3.1!nonanedihydrochloride. The obtained mixture was stirred overnight and asaturated aqueous solution of sodium hydrogencarbonate was poured intothe reaction mixture. The obtained mixture was extracted withdichloromethane twice. The combined organic phases were dried overmagnesium sulfate and freed from the solvent. The residue was purifiedby silica gel column chromatography (5 to 10% methanol/dichloromethane)to give 1.20 g of the title compound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.44-1.52 (m, 2H), 1.55(d, J=7 Hz, 3H),1.83(d, J=2 Hz, 3H), 2.44-2.54(m, 2H), 2.53(s, 3H), 2.63-2.67(m, 2H),3.78-3.82(m, 2H), 3.90-3.96(m, 2H), 4.30(br.s, 2H), 4.72-4.79(m, 1H),4.84-4.91(m, 1H), 6.48(s, 1H), 8.03(s, 1H), 8.88(d, J=8 Hz, 1H)

Example 2

(S)-N-(9-Methyl-3-oxa-9-azabicyclo3.3.1!non-7α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR21##

1.20 g of the (S)-N-(9-methyl-3-oxa-9-azabicyclo3.3.1!non-7α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamideprepared in the Example 1 was dissolved in 3.10 ml of 1N hydrochloricacid, followed by the dilution thereof with distilled water. Theresulting solution was freeze-dried to give 1.24 g of the titlecompound.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.58(d, J=7 Hz, 3H), 1.63-1.71,1.84-1.92(m×2, 2H ), 1.80, 1.81 (d×2, J=2 Hz, 3H), 2.51-2,65(m, 1H),2.70-2.85(m, 1H), 2.82, 2.95(d×2, J=2 Hz, 3H), 3.30-3.50(m, 2H),3.73-3.84, 3.92-4.02(m×2, 2H), 4.30-4.48(m, 2H), 4.49-4.60(m, 1H),4.97-5.03(m, 1H), 6.57(s, 1H), 7.72(s, 1H), 8.55, 8.58 (d×2, J=8 Hz, 1H), 10.90, 11.35(br.s×2, 1H)

MS m/z (FAB): 392 (M⁺ +1)

Example 3

(S)-N-(9-Methyl-9-azabicyclo3.3.1!non-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide

Chemical formula 26! ##STR22##

The title compound was prepared in a similar manner to that of theExample 1.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.05-1.12(m, 2H), 1.23-1.34(m, 2H),1.40-1.55(m, 2H), 1.68(d, J=7 Hz, 3H), 1.73-2.02(m, 2H), 2.45-2.60(m,2H), 2.51(s, 3H), 3.05-3.12(m, 2H), 4.36(br.s, 2H), 4.37-4.47(m, 1H),4.82-4.88(m, 1H), 6.46(s, 1H), 7.65(d, J=7 Hz, 1H), 8.10(s, 1H)

Example 4

(S)-N-(9-Methyl-9-azabicyclo3.3.1!-non-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR23##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.35-2.30(m, 8H), 1.60(d, J=7 Hz,3H), 1.82(s, 3H), 2.44-2.92(m, 2H), 2.75(s, 3H), 3.45-3.72(m, 2H),4.16-4.50 (m, 1H), 4.90-5.08(m, 1H), 6.02, 6.04(s×2, 1H), 6.99,7.04(s×2, 1H), 7.70, 7.87 (d×2, J=7 Hz, 1H), 9.92, 10.91(br.s×2, 1H)

MS m/z (FAB): 390 (M⁺ +1)

Example 5

N-(1-Azabicyclo3.3.1!-non-4α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR24##

The title compound was prepared in a similar manner to that of theExample 1.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 0.90-1.10(m, 1H), 1.35(d, J=7 Hz, 3H),1.70-2.10(m, 6H), 1.70, 1.72(d×2, J=2Hz, 3H), 2.94-3.22 (m, 6H), 4.36(s,2H), 4.40-4.52(m, 1H), 4.88-4.92(m, 1H), 6.48, 6.50(s×2, 1H), 7.84,7.88(d×2, J=6 Hz, 1H), 8.11(s, 1H)

Example 6

N-(1-Azabicyclo3.3.1!-non-4α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR25##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.59(d, J=7 Hz, 3H), 1.64-1.92(m,3H), 1.81, 1.82(d×2, J=2 Hz, 3H), 1.97-2.14(m, 3H), 2.17-2.23(m, 1H),3.36-3.45(m, 6H), 4.30-4.40(m, 1H), 4.97-5.06(m, 1H), 6.62(s, 1H),7.60(s, 1H), 7.78-7.85(m, 1H), 10.85(br.s. 1H)

MS m/z (FAB ): 376 (M⁺ +1)

Example 7

cis-N-(1-Ethoxycarbonyl-3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR26##

The title compound was prepared in a similar manner to that of theExample 1.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.26(t, J=7 Hz, 3H), 1.68, 1.70(d×2, J=7Hz, 3H), 1.72-1.78(m, 2H), 1.82, 1.88(d×2, J=2 Hz, 3H), 2.77-3.00(m,2H), 3.34-3.47(m, 4H), 4.02-4.32(m, 5H), 4.37(br.s, 2H), 4.80-4.87(m,1H), 6.48, 6.50(s×2, 1H), 8.08, 8.10(s×2, 1H), 8.15-8.26(m, 1H)

MS m/z (FAB): 488 (M⁺ +1)

Example 8

cis-N-(3-Methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR27##

2.50 g of thecis-N-(1-ethoxycarbonyl-3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamideprepared in the Example 7 and 4.5 g of potassium hydroxide weredissolved in 2-propanol. The obtained solution was refluxed for 1.5hours and cooled, followed by the addition thereto of water. Theresulting mixture was extracted with 10% 2-propanol/chloroform thrice.The combined organic phases were dried over magnesium sulfate and freedfrom the solvent. The residue was purified by silica gel columnchromatography (5 to 12% methanol/dichloromethane) to give 0.34 g of thetitle compound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.59-1.76(m, 2H), 1.68, 1.69(d×2, J=7Hz, 3H), 1.79, 1.81(d×2, J=2 Hz, 3H), 1.58-2.73(m, 3H), 3.01-3.08(m, 1H)3.26-3.35(m, 2H), 3.39, 3.43(s×2, 3H), 4.15-4.26(m, 1H), 4.45(br.s, 2H),4.77-4.86(m, 1H), 6.48, 6.49(s×2, 1H), 8.07(s, 1H), 8.16, 8.22(d×2, J=7Hz, 1H)

Example 9

cis-N-(3-Methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR28##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.62 (d, J=7 Hz, 3H), 1.67-1.86(m,2H), 1.81(s, 3H), 2.92-3.16(m, 3H), 3.35, 3.39(s×2, 3H), 3.50-3.64(m,2H), 4.16-4.26(m, 1H), 5.00-5.08(m, 1H), 6.59, 6.61(s×2, 1H), 7.71,7.73(s×2, 1H), 8.06(d, J=7 Hz, 1H), 8.21-8.35(m, 1H), 9.28-9.42(m, 1H)

MS m/z (FAB): 366 (M⁺ +1)

Example 10

cis-N- 1-3-(4-Fluorophenoxy)propyl!-3-methoxy-4-piperidinyl!-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR29##

A mixture comprising 0.10 g of thecis-N-(3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide,0.07 g of 3-(4-fluorophenoxy)propyl bromide, 0.20 g of triethylamine and10 ml of DMF was stirred at 50° C. for 2 hours and cooled. Ethyl acetatewas poured into the resulting mixture. The obtained mixture was washedwith water thrice, dried over magnesium sulfate, and freed from thesolvent. The residue was purified by silica gel column chromatography(5% methanol/dichloromethane) to give 0.13 g of the title compound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.68, 1.69(d×2, J=7 Hz, 3H),7.75-2.05(m, 4H), 1.81, 1.82(d×2, J=2 Hz, 3H), 2.07-2.27(m, 2H),2.47-2.62(m, 2H), 2.78-2.87(m, 1H), 3.06-3.21(m, 1H), 3.36, 3.42(s×2,3H), 3.44-3.48(m, 1H), 3.92-3.98(m, 2H), 4.14-4.25(m, 1H), 4.38(br.s,2H), 4.79-4.86(m, 1H), 6.49, 6.50(s×2, 1H), 6.78-6.85(m, 2H),6.91-6.98(m, 2H), 8.09, 8.10(s×2, 1H), 8.17, 8.21(d×2, J=7 Hz, 1H)

Example 11

cis-N- 1-3-14-Fluorophenoxy)propyl!-3-methoxy-4-piperidinyl!-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR30##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.62, 1.63(d×2, J=7 Hz, 3H),1.76-1.98(m, 2H), 1.81, 1.82(d×2, J=2 Hz, 3H), 2.04-2.26(m, 2H),3.07-3.62(m, 5H), 3.39, 3.43(s×2, 3H), 3.66-3.73(m, 1H), 3.82-3.89(m,1H), 3.98-4.04(m, 2H), 4.16-4.26(m, 1H), 4.98-5.05(m, 1H), 6.60,6.62(s×2, 1H), 6.92-6.98(m, 2H), 7.10-7.16(m, 2H), 7.73, 7.74(s×2, 1H),8.06, 8.08 (d×2, J=7 Hz, 1H), 9.32-9.48(m, 1H)

MS m/z (FAB): 518 (M⁺ +1)

Example 12

cis-N-(1-Methyl-3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR31##

The title compound was prepared in a similar manner to that of theExample 10.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.71, 1.72 (d×2, J=7 Hz, 3H),1.75-2.00(m, 2H), 1.82, 1.84(d×2, J=2 Hz, 3H), 2.04-2.17(m, 2H), 2.29,2.30(s×2, 3H), 2.76-2.84(m, 1H), 3.01-3.14(m, 1H), 3.39, 3.46(s×2, 3H),3.40-3.45(m, 1H), 4.10-4.20(m, 1H), 4.36(br.s, 2H), 4.80-4.88(m, 1H),6.53, 6.57(×2, 1H), 8.15(s, 1H), 8.01, 8.01(d×2, J=7 Hz, 1H)

Example 13

cis-N-(1Methyl-3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR32##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.62(d, J=7 Hz, 3H), 1.74-1.92(m,2H), 1.81(s, 3H), 2.74(s, 3H), 3.03-3.84(m, 5H), 3.37, 3.42(s×2, 3H),4.11-4.21(m, 1H), 4.98-5.10(m, 1H), 6.08(s, 2H), 6.59(s, 1H), 7.72(s,1H), 8.01-8.08(m, 1H), 9.16-9.32(m, 1H)

MS m/z (FAB): 380 (M⁺ +1)

Example 14

N-(4-Oxa-1-azabicyclo3.3.1!non-6α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR33##

The title compound was prepared in a similar manner to that of theExample 1.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.72(d, J=7 Hz, 3H), 1.88, 1.86(d×2, J=7Hz, 3H), 1.88-2.05(m, 1H), 2.14-2.24(m, 1H), 2.77-2.84(m, 1H),2.92-3.02(m, 1H), 3.05-3.20(m, 2H), 3.41-3.49(m, 2H), 3.69-3.84(m, 2H),3.95-4.05(m, 1H), 4.19-4.30(m, 1H), 4.51-4.56(m, 2H), 4.83-4.91(m, 1H),6.52, 6.55(s×2, 1H), 8.06(s, 1H), 8.34-8.42(m, 1H)

Example 15

N-(4-Oxa-1-azabicyclo3.3.1!non-6α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR34##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.62(d, J=7 Hz, 3H), 1.82(s, 3H),2.06-2.15(m, 2H), 2.98-3.07(m, 1H), 3.24-4.30(m, 11H), 4.97-5.05(m, 1H),6.60(s, 1H), 7.72(s, 1H), 8.08-8.15(m, 1H), 11.45(br.s, 1H)

MS m/z (FAB): 378 (M⁺ +1)

Example 16

N-((6S)- or (6R)-6β-hydroxy-8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR35##

The same procedure as that of the Example 1 was repeated except that3-amino-6-hydroxy-8-methyl-8-azabicyclo 3 2.1!octane was used as theazabicyclo component. The obtained product was purified by HPLC with acolumn for the separation of optical isomers (Chiralcel OD, a product ofDaicel Chemical Industries. Ltd. 20φ×250 mm) to give the titlecompounds.

    mobile phase: ethanol/n-hexane/triethylamine (10:90:0.5) mixture

The following fraction 1 refers to that of a shorter retention time,while the following fraction 2 refers to that of a longer retentiontime.

<fraction 1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.45-1.52(m, 1H), 1.65-1.74(m, 1H),1.71(d, J=7 Hz, 3H), 1.84(d, J=2 Hz, 3H), 1.97-2.05(m, 1H), 2.23-2.34(m,2H), 2.47-2.54(m, 1H), 2.56(s, 3H), 3.03-3.07(m, 1H), 3.30-3.35(m, 1H),4.19(q, J=7 Hz, 1H), 4.39(br.s, 2H), 4.53(dd, J=3 Hz, 7 Hz, 1H),4.91-4.98(m, 1H), 6.44(s, 1H), 7.86(d, J=6 Hz, 1H), 8.05(s, 1H)

MS m/z (FAB): 392 (M⁺ +1)

<fraction 2>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.42-1.49(m, 1H), 1.67-1.74(m, 1H),1.71(d, J=7 Hz, 3H), 1.86(d, J=2 Hz, 3H), 1.97-2.05(m, 1H), 2.22-2.34(m,2H), 2.48-2.56(m, 1H), 2.56(s, 3H), 3.03-3.06(m, 1H), 3.30-3.34(m, 1H),4.19(q, J=7 Hz, 1H), 4.39(br.s, 2H), 4.54(dd, J=3 Hz, 7 Hz, 1H),4.90-4.97(m, 1H), 6.46(s, 1H), 7.88(d, J=6 Hz, 1H), 8.06(s, 1H)

MS m/z (FAB): 392 (M⁺ +1)

Example 17

N-(DL-6α-Hydroxy-8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR36##

The title compound was obtained as another fraction in a small amount inthe HPLC of the Example 16.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.20-2.10 (m, 4H), 1.66(d, J=7 Hz, 3H),1.87(d, J=2 Hz, 3H), 2.29-2.38(m, 2H), 2.48(s, 3H), 3.10-3.15(m, 1H),3.24-3.30(m, 1H), 4.24-4.34(m, 3H), 4.72-4.78(m, 1H), 4.80-4.87(m, 1H),6.43(s, 1H), 7.95(s, 1H), 8.85(d, J=7 Hz, 1H)

Example 18

(S)-N-(3,9-Dimethyl-3,9-diazabicyclo3.3.1!non-7α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide##STR37##

The title compound was prepared in a similar manner to that of theExample 1.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.43-1.50(m, 2H), 1.58(d, J=7 Hz, 3H),1.83(d, J=2 Hz, 3H), 2.23(s, 3H), 2.38-2.56(m, 4H), 2.51 (s, 3H),2.56-2.62(m, 1H), 2.68-2.74(m, 1H), 2.80-2.88(m, 1H), 4.25(s, 2H),4.50(q, J=6 Hz, 1 Hz), 4.65-4.72(m, 1H), 6.53(s, 1H), 7.68(s, 1H),9.93(3, J=6 Hz), 1H)

Example 19

(S)-N-(3,9-Dimethyl-3,9-diazabicyclo3.3.1!non-7α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidedihydrochloride ##STR38##

The title compound was prepared in a similar manner to that of theExample 2.

MS m/z (FAB): 405 (M⁺ +1)

Example 20

N-(5S)- or (5R)-4-Oxa-1-azabicyclo3.3.1!non-6α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR39##

The product of the Example 14 was separated by HPLC with a column forthe separation of optical isomers (Chiralcel OD, a product of DaicelChemical inductries, Ltd., 20φ×250 mm) to give the title compounds.

    mobile phase: ethanol/n-hexane/triethylamine (20:80:0.5) mixture

The following fraction 1 refers to that of a shorter retention time,while the following fraction 2 refers to that of a longer retentiontime.

The isomers thus prepared were each converted into their respectivehydrochlorides according to the process of the Example 2.

<hydrochloride of fraction 1>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.61(3, J=7 Hz, 3H), 1.81(d, J=2 Hz,3H), 2.02-2.18(m, 2H), 3.26-3.46(m, 4H), 3.49-3.58(m, 1H), 3.67-3.75(m,1H), 3.91-4.04(m, 2H), 4.08-4.12(m, 1H), 4.17-4.25(m, 1H), 4.96-5.08(m,1H), 6.08(br.s, 2H), 6.59(2, 1H), 7.72(s, 1H), 8.12(d, J=7Hz, 1H),10.57(br.s, 1H)

MS m/z (FAB): 378 (M⁺ +1)

α!_(D) ²³ =-63.46° (C=1, MeOH)

<hydrochloride of fraction 2>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.61(d, J=7 Hz, 3H), 1.82(d, J=2 Hz,3H), 2.08˜2.17(m, 2H), 3.26-3.44(m, 4H), 3.47-3.56(m, 1H), 3.67-3.74(m,1H), 3.90-4.03(m, 2H), 4.04-4.08(m, 1H), 4.16-4.25(m, 1H), 4.97-5.05(m,1H), 6.59(s, 1H), 7.71(s, 1H), 8.11(d, J=7 Hz, 1H), 11.07(br.s, 1H)

MS m/z (FAB): 378 (M⁺ +1)

α!_(D) ²³ =-169.90° (C=1, MeOH)

Example 21

N-(4-Oxa-1-azabicyclo3.3.1!non-6β-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR40##

The title compound was prepared as a minor product in themass-production of the Example 20.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.53˜1.64(m, 1H), 1.70(d, J=7 Hz, 3H),1.85(d, J=2 Hz, 3H), 2.54-2.66(m, 1H), 2.94-3.05(m, 2H), 3.19-3.30(m,1H), 3.37-3.60(m, 2H), 3.68-3.80(m, 2H), 4.02-4.10(m, 1H), 4.40-4.53(m,2H), 4.78-4.92(m, 1H), 6.46(s, 1H), 8.02(d, J=6 Hz, 1H), 8.10(s, 1H)

Example 22

N-(4-Oxa-1-azabicyclo3.3.1!non-6β-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR41##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.59(d, J=7 Hz, 3H), 1.74-1.85(m,1H), 1.82(d, J=2 Hz, 3H), 2.56-2.71(m, 1H), 3.18-3.78(m, 4H),3.84-4.12(m, 6H), 4.88-5.06(m, 1H), 5.96, 6.10(br.s×2, 2H), 6.58,6.59(s×2, 1H), 7.48, 7.49(×2, 1H), 7.91, 7.95(d×2, J=7 Hz, 1H),10.90(br.s, 1H)

MS m/z (FAB): 378 (M⁺ +1)

Example 23

N-((6R)- or (6S)-6β-Methoxy-8-methyl-8-azabicyclo3.2.1!oct-3β-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR42##

The same procedure as that of the Example 1 was repeated except that3-amino-6-methoxy-8-methyl-8-azabicyclo 3.2.1!octane was used as theazabicyclo component. The obtained product was separated by HPLC with acolumn for the separation of optical isomers (Chiralcel OJ, a product ofDaicel Chemical Industries, Ltd., mobile phase:ethanol/n-hexane/triethylamine (10:90:0.5) mixture). The first fractionwas further separated by HPLC with Chiralcel OD (a product of DaicelChemical Industries, Ltd., mobile phase: ethanol/n-hexane/triethylamine(10:9:0.5) mixture) to give the title compounds.

The obtained fractions were numbered 1, 2 and 3 in the order ofincreasing retention time.

<fraction 1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.54-1.66(m, 2H), 1.66(d, J=7 Hz, 3H),1.77-1.82(m, 1H), 1.83(d, J=2 Hz, 3H), 1.87-1.95(m, 1H), 2.05-2.19(m,2H), 2.51(s, 3H), 3.23-3.26(m, 1H), 3.29(s, 3H), 3.36-3.41(m, 1H),3.92-3.96(m, 1H), 3.99-4.12(m, 1H), 4.38(br.s, 2H), 4.78-4.85(m, 1H),6.46(s, 1H), 7.62(d, J=6 Hz, 1H), 8.02(s, 1H)

<fraction 3>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.55-1.64(m, 2H), 1.67(d, J=7 Hz, 3H),1.75-1.81(m, 1H), 1.83(d, J=2 Hz, 3H), 1.91-2.19(m, 3H), 2.51(s, 3H),3.23-3.27(m, 1H), 3.29(s, 3H), 3.35-3.40(m, 1H), 3.93-3.97(m, 1H),3.98-4.14(m, 1H), 4.36(br.s, 2H) 4.78-4.85(m, 1H), 6.45(s, 1H), 7.61(d,J=6 Hz, 1H), 8.03(s, 1H)

Example 24

N-((6S)- or (6R)-6β-Methoxy-8-methyl-8-azabicyclo3.2.1!oct-3β-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR43##

The fractions 1 and 3 of the Example 23 were each treated according tothe process of the Example 2 to give the title compounds.

<hydrochloride of fraction 1 of Example 23>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.64(d, J=7 Hz, 3H), 1.82(d, J=2 Hz,3H), 1.95-2.27(m, 5H), 2.42-2.50(m, 1H), 2.75(d, J=6 Hz, 3H), 3.26(s,3H), 3.97-4.11(m, 4H), 4.95-5.02(m, 1H), 6.58(s, 1H), 7.64(s, 1H),7.65(d, J=7 Hz, 1H), 10.92(m, 1H)

MS m/z (FAB): 406 (M⁺ +1)

<hydrochloride of fraction 3 of Example 23>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.64(d, J=7 Hz, 3H), 1.82(d, J=2 Hz,3H), 1.92-2.08(m, 3H), 2.10-2.17(m, 1H), 2.20-2.28(m, 1H), 2.42-2.49(m,1H), 2.76(d, J=6 Hz, 3H), 3.26(s, 3H), 3.95-4.12 (m, 4H), 4.95-5.03(m,1H), 6.05(br.s, 2H), 6.58(s, 1H), 7.64(s, 1H), 7.65(d, J=7 Hz, 1H),10.75(m, 1H)

MS m/z (FAB): 406 (M⁺ +1)

N-(6α-Methoxy-8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR44##

The title compound was obtained as the fraction 2 in the HPLC of theExample 23.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.64, 1.67(d×2, J=7 Hz, 3H), 1.80,1.86(d×2, J=2 Hz, 3H), 1.68-2.00(m, 4H), 2.21-2.42(m, 3H), 2.43,2.44(s×2, 3H), 3.05-3.10(m, 1H), 3.22-3.26(m, 1H), 3.33, 3.45(s×2, 3H),4.13-4.20(m, 1H), 4.27, 4.30 (br.s×2, 2H), 4.67, 4.78(m×2, 1H), 6.45,6.60 (s×2, 1H), 7.81, 7.83 (s×2, 1H), 8.41, 8.44(d×2, J=6 Hz, 1H)

Example 26

N-(6α-Methoxy-8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR45##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.55, 1.58(d×2, J=7 Hz, 3H), 1.77,1.84(d×2, J=2 Hz, 3H), 1.80-2.11(m, 3H), 2.42-2.53(m, 1H), 2.56-2.70(m,4H), 2.76-2.79(m, 1H), 3.31, 3.42 (s×2, 3H), 3.61-4.48(m, 4H),4.82-5.00(m, 1H), 6.55, 6.62(s×2, 1H), 7.50, 7.52(s×2, 1H), 8.07-8.18(m,1H), 10.55, 10.90(m×2, 1H)

MS m/z (FAB): 406 (M⁺ +1)

Example 27

N-((6S)- or (6R)-6β-Methoxy-8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR46##

The second fraction obtained by the HPLC with a column for theseparation of optical isomers (Chiralcel OJ) in the Example 23 wasfurther separated with Chiralcel OD under the same conditions as thoseof the Example 23 to give the title compounds.

The obtained Fractions were numbered 1 and 2 in the order of increasingretention time.

<fraction 1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.70(d, J=7 Hz, 3H), 1.84(d, J=2 Hz,3H), 2.06-2.16(m, 2H), 2.21-2.39(m, 4H), 2.51(s, 3H), 3.16-3.20(m, 1H),3.26(s, 3H), 3.28-3.34(m, 1H), 4.08-4.13(m, 1H), 4.17(q, J=7 Hz, 1H),4.40(br.s, 2H), 4.90-4.98(m, 1H), 6.47(s, 1H), 7.87(d, J=6 Hz, 1H),8.08(s, 1H)

<fraction 2>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.71(d, J=7 Hz, 3H), 1.83(d, J=2 Hz,3H), 2.05-2.12(m, 1H), 2.12-2.37(m, 3H), 2.51(s, 3H), 3.17-3.21(m, 1H),3.26-3.34(m, 1H), 3.28(s, 3H), 4.08-4.13(m, 1H), 4.16(q, J=7 Hz, 1H),4.40(br.s, 2H), 4.92-4.98(m, 1H), 6.44(s, 1H), 7.88(d, J=6 Hz, 1H),8.08(s, 1H)

Example 28

N-((6S)- or (6R)-6β-Methoxy-8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR47##

The fractions 1 and 2 obtained in the Example 27 were each treated in asimilar manner to that of the Example 2 to give the title compounds.

<hydrochloride of fraction 1 of Example 27>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.62(d, J=7 Hz, 3H), 1.81(d, J=2 Hz,3H), 1.84-2.34(m, 3H), 2.41-2.78(m, 5H), 3.08-3.45(m, 1H), 3.24(s, 3H),3.58-3.76(m, 1H), 3.84-4.00(m, 2H), 4.10-4.26 (m, 1H), 5.05-5.13(m, 1H),6.00(br.s, 2H), 6.61(s, 1H), 7.60(s, 1H), 7.79(d, J=7 Hz, 1H)

MS m/z (FAB): 406 (M⁺ +1)

<hydrochloride of fraction 2 of Example 27>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.62(d, J=7 Hz, 3H), 1.82(d, J=2 Hz,3H), 1.98-2.05(m, 1H), 2.10-2.17(m, 1H), 2.24-2.32(m, 1H), 2.46-2.56(m,1H), 2.61-2.69(m, 1H), 2.78(d, J=6 Hz, 3H), 3.25(s, 3H), 3.32-3.54(m,1H), 3.90-3.97(m, 1H), 3.99-4.06(m, 2H), 4.22-4.27(m, 1H), 5.05-5.13(m,1H), 6.00(br.s, 2H), 6.60(s, 1H), 7.59(s, 1H), 7.78(d, J=7 Hz, 1H),10.58(br.s, 1H)

MS m/z (FAB): 406 (M⁺ +1)

Example 29

N-(8-Azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR48##

0.75 g of (S)-N-(8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide,0.51 g of 2,2,2-trichloroethyl chlorocarbonate and 0.41 g of potassiumcarbonate were added to toluene. The obtained mixture was refluxed for 3hours and cooled, followed by the addition thereto of dichloromethane.The resulting mixture was washed with 1N hydrochloric acid, dried overmagnesium sulfate, and freed from the solvent. The residue was purifiedby silica gel column chromatography (ethyl acetate/n-hexane (1:4)mixture) to give 0.50 g of(S)-N-(8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo3.2.1!oct-3α-yl)-5-chloro-2-(1-methyl-2-butynyl)oxy-4-(2,2,2-trichloroethoxycarbonylamino)benzamide.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.71(d, J=7 Hz, 3H), 1.83(d, J=2 Hz,3H), 1.84-1.97(m, 2H), 2.00-2.16(m, 4H), 2.28-2.38(m, 2H), 4.33(q, J=7Hz, 1H), 4.36-4.44(m, 2H), 4.65-4.93(m, 2H), 4.86(d, J=2 Hz, 2H),5.10-5.18(m, 1H), 7.53(s, 1H), 8.17(br.s, 1H), 8.22(s, 1H), 8.24(br.s,1H)

This compound was stirred in 90% acetic acid in the presence of powderedzinc at room temperature overnight and filtered. The filtrate was freedfrom the solvent, followed by the addition thereto of 1N sodiumhydroxide. The resulting mixture was extracted with chloroform thriceand the combined organic phases were dried over magnesium sulfate, andfreed from the solvent. The residue was purified by thin-layerchromatography (15% methanol/chloroform) to give 30 mg of the titlecompound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.68(d, J=6.5 Hz, 3H), 1.83(d, J=2 Hz,3H), 1.85-1.95(m, 2H), 1.98-2.09(m, 4H), 2.23-2.33(m, 2H), 3.62-3.77(m,2H), 4.28(q, J=6 Hz, 1H), 4.38(br.s, 2H), 4.90-4.98(m, 1H), 6.43(s, 1H),8.02(d, J=6 Hz, 1H), 8.08(s, 1H)

MS m/z (FAB): 362 (M⁺ +1)

Example 30

N-((5S)- or (5R)-1-Azabicyclo3.3.1!non-4α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR49##

The product of the Example 5 was separated by HPLC with a column for theseparation of optical isomers (Chiralcel OD, a produce of DaicelChemical Industries, Ltd., mobile phase: ethanol/n-hexane/triethylamine(85:15:0.5) mixture) to give the title compounds.

The following fraction 1 refers to that of a shorter retention time,while the following fraction 2 refers to that of a longer retentiontime.

<fraction 1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.40-2.01(m, 7H), 1.68(d, J=7 Hz, 3H),1.84(d, J=4 Hz, 3H), 2.90-3.22(m, 6H), 4.40(br.s, 2H), 4.33-4.54(m, 1H),4.85-4.93(m, 1H), 6.48(s, 1H), 7.84(d, J=8 Hz, 1H), 8.50(s, 1H)

<fraction 2>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.39-2.07 (m, 7H), 1.67(d, J=7 Hz, 3H),1.84(d, J=4 Hz, 3H), 2.90-3.22(m, 6H), 4.39(br.s, 2H), 4.33-4.52 (m,1H), 4.85-4.93(m, 1H), 6.50(s, 1H), 7.84(d, J=8 Hz, 1H), 8.50(s, 1H)

Example -

N-((5S)- or (5R)-1-Azabicyclo3.3.1!non-4α-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR50##

The fractions 1 and 2 obtained in the Example 30 were each treated in asimilar manner to that of the Example 2 to give the title compounds.

<hydrochloride of fraction 1 of Example 30>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.59(d, J=7 Hz, 3H), 1.62-2.22(m,7H), 1.83(d, J=4 Hz, 3H), 3.19-3.42(m, 6H), 4.30-4.40(m, 1H),4.97-5.06(m, 1H), 6.60(s, 1H), 7.60(s, 1H), 7.82(d, J=8 Hz, 1H),10.70(br.s, 1H)

MS m/z (FAB): 376 (M⁺ +1)

α!_(D) ²³ =-112.38° (C=0.2, MeOH),

<hydrochloride of fraction 2 of Example 30>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.58(d, J=7 Hz, 3H), 1.62-2.23(m,7H), 1.81(d, J=4 Hz, 3H), 3.16-3.40(m, 6H), 4.30-4.39(m, 1H),4.97-5.06(m, 1H), 6.60(s, 1H), 7.60(s, 1H), 7.82(d, J=8 Hz, 1H),10.65(br.s, 1H)

MS m/z (FAB): 376 (M⁺ +1)

α!_(D) ²³ =-80.86° (C=1, MeOH)

Example 32

N-(1-Azabicyclo3.3.1!non-4β-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide##STR51##

The title compound was obtained as another fraction in the HPLC of theExample 30.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.47-2.42(m, 7H), 1.70, 1.72(d×2, J=9Hz, 3H), 1.84, 1.85(d×2, J=4 Hz, 3H), 2.81-2.88(m, 1H), 2.98-3.33(m,5H), 4.32-4.45(m, 1H), 4.37(br.s, 2H), 4.86-4.93(m, 1H), 6.47(s, 1H),8.48(s, 1H), 8.18(d, J=9 Hz, 1H)

Example 33

N-(1-Azabicyclo3.3.1!non-4β-yl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR52##

The title compound was prepared in a similar manner to that of theExample 2.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 1.58(d, J=8 Hz, 3H), 1.62-1.92(m,4H), 1.82(d, J=4 Hz, 3H), 2.06-2.20(m, 2H), 2.38-2.50(m, 1H),3.00-3.40(m, 6H), 4.02-4.08(m, 1H), 4.92-4.98(m, 1H), 6.59(s, 1H),7.52(s, 1H), 7.86-8.02(br.s, 1H), 10.74(br.s, 1H)

MS m/z (FAB): 376 (M⁺ +1)

Example 34

(S)-N-(3-Methyl-3-Azabicyclo 3.2.1!oct-8α- or8β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide ##STR53##

700 mg of (S)-4-amino-5-chloro-2- (1-methyl-2-butynyl)oxy!benzoic acidand 740 mg of 8-amino-3-methyl-3-azabicyclo 3.2.1!octane were dissolvedin 25 ml of pyridine. 370 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafterabbreviated to "WSC.HCl") and 590 mg of 1-hydroxybenzotriazole (HOBT)were added to the obtained solution under stirring at room temperature.The obtained mixture was stirred overnight and distilled in a vacuum toremove the solvent. The residue was extracted with a 2N aqueous solutionof sodium hydroxide and chloroform. The organic phase was dried overanhydrous magnesium sulfate and concentrated in a vacuum. The residuewas purified by silica gel column chromatography (1 to 10 to 20%methanol/chloroform) to give two products. The first eluate was composedof the 8α isomer (264 mg), while the second eluate was composed of the8β isomer (18 mg).

<8α isomer>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.15(s, 1H), 8.03(d, J=6 Hz, 1H),6.05(s, 1H), 4.95(dd, J=6.4 Hz, 2.0 Hz, 1H), 4.37(br.s, 2H), 4.04-4.09(dd, J=6.6 Hz, 5.2 Hz, 1H), 2.56-2.62(br.d, J=11.0 Hz, 2H), 2.32-2.44(m,2H), 2.30(s, 3H), 2.25(br.s, 2H), 2.87-1.76(m+d, J=2.0 Hz, 7H), 1.74(d,J=6.4 Hz, 3H)

<8β isomer>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.10(s, 1H), 7.69(d, J=6.8 Hz, 1H),6.46(s, 1H), 4.85-4.92(dd, J=6.6 Hz, 2.0 Hz, 1H), 4.37-4.40(br.s, 2H),4.02-4.06 (d, J=7.0 Hz, 1H), 2.83-2.86(br.d, J=7.8 Hz, 2H),2.24-2.42(m+s, 7H), 1.80-1.94(m+d, J=2 Hz, 7H), 1.67(d, J=6.4 Hz, 3H)

Example 35

(S)-N-(3-Methyl-3-azabicyclo3.2.1!oct-8α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR54##

264 mg of (S)-N-(3-methyl-3-azabicyclo3.2.1!oct-8α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide wasdissolved in ethanol, followed by the addition thereto of 140 μl of a20% ethanolic solution of hydrochloric acid at room temperature. Theobtained solution was concentrated in a vacuum, followed by the additionthereto of diethyl ether. The salt thus precipitated was recovered byfiltration. 228 mg of the title compound was obtained.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 10.10(br.s, 1H), 7.99(d, J=5.1 Hz,1H), 7.55(s, 1H), 6.62 (s, 1H), 5.01(br.d, J=2.0 Hz, 1H), 3.60-3.80(m,3H), 3.15-3.25(t, J=12.0 Hz, 2H), 3.08-2.99(t, J=12.0 Hz, 2H), 2.66(d,J=4.6 Hz, 3H), 2.41(br.s, 2H), 1.95-2.02(d, J=9.3 Hz, 2H), 1.78-1.87(m,5H), 1.59(d, J=6.4 Hz, 3H)

MS m/z (FAB): 376 (M⁺ +1)

Example 36

(S)-N-(3-Methyl-3-azabicyclo3.2.1!oct-8β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR55##

The title compound was prepared in a similar manner to that of theExample 35.

¹ H-NNR (400 MHz, d₆ -DMSO) δ ppm: 9.51(br.s, 1H), 7.65(s, 1H), 7.58(d,J=6.4 Hz), 6.58(s, 1H), 4.98-5.05(dd, J=6.4 Hz, 2.0 Hz, 1H),4.13-4.17(br.d, J=6.7 Hz, 1H), 3.53-3.80(br.s, 2H), 3.26-3.32(m, 2H),3.15-3.23(m, 2H), 2.65-2.70(d,m J=4.6 Hz, 3H), 2.33-2.38(br.s, 2H),1.78-1.98(m, 7H), 1.58(d, J=6.4 Hz, 3H)

MS m/z (FAB): 376 (M⁺ +1)

Example 37

(S)-N-(3-Isopropyl-3-azabicyclo3.2.1!oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide##STR56##

600 mg of (S)-4-amino-5-chloro-2-{(1-methyl-2-butynyl)oxy benzoic acidand 1.03 g of 8-amino-3-isopropyl-3-azabicyclo 3.2.1!octane weredissolved 6 ml of pyridine. 1.26 g of dicyclohexylcarbodiimide (DCC) wasadded to the obtained solution under stirring at room temperature. Theresulting mixture was stirred overnight, followed by the additionthereto of 6 ml of water. Insolubles were filtered out and the filtratewas basified with an aqueous solution of sodium hydroxide and extractedwith chloroform. The organic phase was dried over anhydrous magnesiumsulfate and freed from the solvent by distillation. The residue waspurified by silicagel column chromatography (5% methanol/chloroform) andthen by preparative thin-layer chromatography to give 40 mg of the titlecompound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.14(s, 1H), 8.04(d, J=6.0 Hz, 1H),6.47(s, 1H), 4.92(m, 1H), 4.36(br.s, 2H), 4.00(m, 1H), 2.40-2.69(m, 5H),2.20-2.55(m, 2H), 1.82(s, 3H), 1.68-1.78(m, 7H), 1.02(d, J=6.4 Hz, 6H)

Example 38

(S)-N-(3-Isopropyl-3-azabicyclo3.2.1!oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR57##

The title compound was prepared in a similar manner to that of theExample 35.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 9.10(br.s, 1H), 7.98(d, J=4.6 Hz),7.59(s, 1H), 6.60(s, 1H), 6.00(br.s, 2H), 5.03(m, 1H), 3.67(m, 1H),3.45-2.95(m, 7H), 2.54-2.50(m, 2H), 1.96-2.75(m, 5H), 1.57(d, J=6.0 Hz,3H), 1.26(d, J=6.4 Hz, 6H)

MS m/z (FAB): 404 (M⁺ +1)

Example 39

(S)-N-(3-Benzyl-3-azabicyclo3.2.1!oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide##STR58##

The condensation of 530 mg of (S)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxy!benzoic acid with 850 mg of8-amino-3-benzylazabicyclo 3.2.1!octane was conducted in a similarmanner to that of the Example 34 by the use of WSC.HCl and1-hydroxybenzotriazole (HOBT). The product was purified by silica gelcolumn chromatography (5% methanol/chloroform) to give 220 mg of thetitle compound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.14(s, 1H), 8.07(d, J=6.6 Hz, 1H),7.36-7.21(m, 5H), 6.52(s, 1H), 4.97(m, 1H), 4.39(s, 2H), 4.10(m, 1H),3.53(s, 2H), 2.61-2.55(m, 2H), 2.48-2.40(m, 2H), 2.21(br.s, 2H),2.90-2.64(m, 10H)

MS m/z (FAB): 452 (M⁺ +1)

Example 40

(S)-N-(3-Benzyl-3-azabicyclo3.2.1!oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR59##

The title compound was prepared in a similar manner to that of theExample 35.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 7.89(d, J=4.2 Hz, 1H), 7.66-7.62(m,2H), 7.49(s, 1H), 7.40-7.35(m, 3H), 6.60(s, 1H), 5.97(br.s, 2H), 4.95(m,1H), 4.23(br.s, 2H), 3.65(m, 1H), 3.30-3.18 (m, 2H), 3.17-2.97 (m, 4H),2.10-1.96(m, 2H), 1.90-1.66(m, 5H), 1.57(d, J=6.4 Hz, 3H)

MS m/z (FAB): 452 (M⁺ +1)

Example 41

N-(8-Methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide##STR60##

600 mg of 4-amino-5-chloro-2- (1-ethoxyethyl-2-butynyl)oxy!benzoic acidand 490 mg of endo-3-amino-8-methyl-8-azabicyclo 3.2.1!octane weredissolved in 12 ml of pyridine, followed by the addition thereto of 210mg of WSC.HCl and 350 mg of 1-hydroxybenzotriazole (HOBT) at roomtemperature. The obtained mixture was stirred overnight and freed fromthe solvent by vacuum distillation. The residue was extracted with anaqueous solution of sodium hydroxide and chloroform. The organic phasewas dried over anhydrous magnesium sulfate and concentrated in a vacuum.The residue was purified by silica gel column chromatography (10%methanol/chloroform) to give 630 mg of the title compound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.09(s, 1H), 7.98(d, J=6.2 Hz, 1H),6.51(s, 1H) 5.05(td, J=4.9 Hz, 2.0 Hz, 1H), 4.35(s, 2H), 4.22(q, J=6.6Hz, 1H), 3.64-3.59(m, 2H), 3.52-3.45(m, 2H), 3.16(br.s, 2H), 2.31(s,3H), 2.32-2.23(m, 3H), 2.17-2.07(m, 3H), 1.92-1.68(m, 7H), 1.20(t, J=4.4Hz, 3H)

Example 42

N-(8-Methyl-8-azabicyclo3.2.1!oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR61##

The title compound was prepared in a similar manner to that of theExample 35.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 10.7(br.s, 1H), 7.88(d, J=4.9 Hz,1H), 7.61(s, 1H), 6.62(s, 1H), 5.02(br.s, 1H), 3.97(m, 1H), 3.96(br.s,2H), 3.53(t, J=6.0 Hz, 2H), 3.39(q, J=7.0 Hz, 2H), 2.61(d, J=5.1 Hz,3H), 2.60-2.45(m, 2H), 2.29-1.94(m, 10H), 1.83(s, 3H), 1.08(t, J=7.0 Hz,3H)

MS m/z (FAB): 434 (M⁺ +1)

Example 43

(S)-N-(3,7-Dimethyl-3,7-diazabicyclo3.3.1!non-9-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide##STR62##

A solution of 546 mg of (S)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxy!benzoic acid and 0.9 ml of triethylamine in 10ml of dichloromethane was cooled with ice, followed by the additionthereto of 0.225 ml of ethyl chloroformate. The obtained mixture wasstirred for 10 minutes, while the temperature was brought to roomtemperature. 400 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo3.3.1!nonane was added to the resulting mixture at room temperature. Theobtained mixture was stirred for 30 minutes, followed by the additionthereto of 200 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo 3.3.1!nonaneat room temperature. The obtained mixture was stirred for one hour,followed by the addition thereto of dichloromethane and water. The pH ofthe aqueous layer was adjusted to 10 or above with a 2.5N aqueoussolution of sodium hydroxide. The organic phase was recovered, driedover anhydrous magnesium sulfate, and concentrated in a vacuum. Theresidue was purified by silica gel column chromatography (with 0 to 10to 20% methanol/chloroform and then with chloroform/methanol/aqueousammonia (75/25/1.5) to give 650 mg of the title compound.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.09(s, 1H), 8.07(d, J=8.0 Hz, 1H),6.47(s, 1H), 4.94-4.87(m, 1H), 4.35(s, 2H), 4.07-4.02(m, 1H), 3.01(br.d,J=10.0 Hz, 2H), 2.80(br.d, J=10.2 Hz, 2H), 2.60-2.49(m, 2H), 2.39(br.d,J=10.0 Hz, 2H), 2.24(s, 3H), 2.23(s, 3H), 2.04(s, 2H), 1.81(s, 3H),1.70(d, J=7.0 Hz, 3H)

Example 44

(S)-N-(3,7-Dimethyl-3,7-diazabicyclo3.3.1!non-9-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR63##

The title compound was prepared in a similar manner to that of theExample 35.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 7.88(d, J=6.2 Hz, 1H), 7.64(s, 1H),6.63(s, 1H), 6.05(br.s, 2H), 5.05(m, 1H), 4.07(m, 1H), 3.51-3.41(m, 2H),3.15-3.01(m, 4H), 2.75-2.64(m, 2H), 2.55(s, 3H), 2.35(s, 3H), 2.19(br.s,2H), 1.82(d, J=2.0 Hz, 3H), 1.62(d, J=6.2 Hz, 3H)

MS m/z (FAB): 405 (M⁺ +1)

Example 45

(S)-N-(1-Benzyl-3-pyrrolidyl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide##STR64##

The title compound was prepared in a similar manner to that of theExample 43.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.06(s, 1H), 8.02(d, J=7.0 Hz, 1H),7.35-7.18(m, 5H), 4.75(s, 1H), 4.85-4.77(m, 1H), 4.63-4.54(m, 1H),4.33(br.s, 2H), 3.62(s+s, 2H), 2.86-2.52(m, 4H), 2.41-2.25(m, 2H),1.83(d+d, J=2.2 Hz, 3H), 1.65(d+d, J=6.2 Hz, 3H)

Example 46

(S)-N-(1-Benzyl-3-pyrrolidyl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR65##

The title compound was prepared in a similar manner to that of theExample 35.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 10.75(br.s)+10.61(br.s)(1H), 7.96(d,J=7.0 Hz)+7.89(m)(1H), 7.60-7.40(m, 6H), 6.57(d, J=7.7 Hz)+6.55(d, J=7.7Hz) (1H), 6.04(br.s, 2H), 4.94(m, 1H), 4.63-4.28(m, 3H), 3.72-2.96(m,6H), 1.82-1.77(m, 3H), 1.63-1.55(m, 3H)

MS m/z (FAB): 412 (M⁺ +1)

Example 47

(S)-N-(3-Oxa-7-methyl-7-azabicyclo 3.3.1!non-9α- or9β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide ##STR66##

The title compound was prepared in a similar manner to that of theExample 43. The product was purified by silica gel column chromatography(10% methanol/chloroform) to give two fractions. The following fraction1 refers to that of a shorter retention time, while the followingfraction 2 refers to that of a longer retention time.

<fraction 1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.09(s, 1H), 8.03(d, J=6.6 Hz, 1H),6.48(s, 1H), 5.00-4.89(m, 1H), 4.43(br.s, 2H), 4.33-4.27(m, 1H), 4.08(d,J=11.4 Hz, 2H), 3.90(d, J=11.4 Hz, 2H), 2.94(d, J=11.7 Hz, 2H), 2.57(t,J=11.5 Hz, 2H), 2.31(s, 3H), 1.94(s, 2H), 1.83(s, 3H), 1.72(d, J=6.4 Hz,3H)

<fraction 2>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.27(d, J=7.3 Hz, 1H), 8.09(s, 1H),6.47(s, 1H), 4.96-4.88(m, 1H) 4.43(br.s, 2H), 4.20-4.13(m, 1H),4.06-3.95(m, 2H), 3.90(d, J=11.9 Hz, 2H), 3.14(d, J=11.4 Hz, 2H),2.50(d, J=11.4 Hz, 2H), 2.32(s, 3H), 1.87(s, 2H), 1.84(s, 3H), 1.69(d,J=6.4 Hz, 3H)

Example 48

(S)-N-(3-Oxa-7-methyl-7-azabicyclo 3.3.1!non-9α- or9β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide hydrochloride##STR67##

The fractions 1 and 2 prepared in the Example 47 were each treated in asimilar manner to that of the Example 35 to give the title compounds.

<hydrochloride of fraction 1 of Example 47>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 8.61(br.s, 1H), 7.92(d, J=5.7 Hz,1H), 7.51(s, 1H), 6.62(s, 1H), 4.99-4.92(m, 1H), 4.17-4.11(m, 1H),4.09(d. J=11.0 Hz, 2H), 3.90-3.48(m, 6H), 3.28-3.17(m, 2H), 2.72(d,J=4.8 Hz, 3H), 2.19(br.s, 2H), 1.82(d, J=2 Hz, 3H), 1.58(d, J=6.4 Hz,3H)

MS m/z (FAB): 392 (M⁺ +1)

<hydrochloride of fraction 2 of Example 47>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 8.71(br.s, 1H), 8.09(d, J=6.2 Hz,1H), 7.65(s, 1H), 6.64(s, 1H), 5.11-5.03(m, 1H), 4.29-4.24(m, 1H),4.05-3.60(m, 8H), 3.48-3.38(m, 2H), 2.74(d, J=4.6 Hz, 3H), 2.12-2.04(m,2H), 1.82(d, J=1.8 Hz, 3H), 1.61(d, J=6.4 Hz, 3H)

MS m/z (FAB): 392 (M⁺ +1)

Example 49

(S)-N-(3-Ethoxy-9-methyl-9-azabicyclo 3.3.1!non-9α- (or9β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide ##STR68##

The title compounds were prepared in a similar manner to that of theExample 43. The product was subjected to HPLC with a chiral column(Chiralcel OJ, a product of Daicel Chemical Industries, Ltd. ) andeluted with a mobile phase comprising ethanol, hexane and triethylamineat a ratio of 9:1:0.01 to give two fractions. The following fraction 1refers to that of a shorter retention time, while the following fraction2 refers to that of a longer retention time.

<fraction 1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.55(s, 1H), 7.60(d, J=7.7 Hz, 1H),6.46(s, 1H), 4.86-4.79(m, 1H), 4.48-4.32(m, 3H), 4.01(quint., J=8.6 Hz,1H), 3.55(q, J=7.1 Hz, 2H), 3.08(br.s, 2H), 2.51(s, 3H), 2.03(td, J=5.9,14.8 Hz, 2H), 1.95-1.81(m, 5H), 1.80-1.64(m, 7H), 1.20(t, J=7.1 Hz, 3H)

<fraction 2>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.07(s, 1H), 7.57(d, J=7.1 Hz, 1H),6.48(s, 1H), 4.88-4.80(m, 1H), 4.40-4.29(m, 3H), 3.89-3.78(m, 1H),3.50(q, J=7.1 Hz, 2H), 3.21(br.d, J=9.6 Hz, 2H), 2.64-2.50(m, 2H),2.42(s, 3H), 1.85(s, 3H), 1.81-1.55(m, 9H), 1.20(t, J=7.1 Hz, 3H)

Example 50

(S)-N-(3-Ethoxy-9-methyl-9-azabicyclo 3.3.1!non-9α- or9β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide hydrochloride##STR69##

The fractions 1 and 2 prepared in the Example 49 were each treated in asimilar manner to that of the Example 35 to give the title compounds.

<hydrochloride of fraction 1 of Example 49>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 11.08(br.s)+10.66(br.s)(1H), 7.71(d,J=7.3 Hz)+7.63(d, J=7.3 Hz)(1H), 7.66(s)+7.55(s)(1H), 6.59(s, 1H),5.02-4.87(m, 1H), 4.38-4.20(m, 1H), 4.04-3.90(m, 1H), 3.62(br.s, 2H),3.54-3.35(m, 4H), 2.86(d, J=4.9 Hz)+2.79(d, J=4.9 Hz)(3H), 2.31-1.84(m,8H), 1.82(s, 3H), 1.65(d, J=6.4 Hz)+1.60(d, J=6.4 Hz) (3H), 1.07(t, J=7Hz, 3H)

MS m/z (FAB): 434 (M⁺ +1)

<hydrochloride of fraction 2 of Example 49>

1H-NMR (400 MHz, d₆ -DMSO) δ ppm: 10.67(br.s)+9.76(br.s)(1H), 7.88(d,J=6.6 Hz)+7.67(d, J=6.6 Hz) (1H), 7.66(s)+(7.60(s)(1H),6.61(s)+6.59(s)(1H), 5.04-4.90(m, 1H), 4.40-4.03(m, 2H), 3.74-3.32(m,6H), 2.78 (d, J=4.8 Hz, 3H), 2.61-2.45(m, 2H), 2.16-1.66(m, 9H), 1.53(d,J=6.2 Hz)+1.52(d, J=6.2 Hz) (3H), 1.09(t, J=7.0 Hz)+1.03(t, J=7.0 Hz)(3H)

MS m/z (FAB): 434 (M⁺ +1)

Example 51

(S)-N-(8-Methyl-8-azabicyclo 3.2.1!oct-2α- or2β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide ##STR70##

500 mg of (S)-4-amino-5-chloro-2- (1-methyl-2-butynyl)oxy!benzoic acidand 553 mg of 2-amino-8-methyl-8-azabicyclo 3.2.1!octane were dissolvedin 5 ml of pyridine, followed by the addition thereto of 812 mg ofdicyclohexylcarbodiimide (DCC) at room temperature. The obtained mixturewas stirred overnight, followed by the addition thereto of 5 ml ofwater. Insolubles were filtered out and the filtrate as basified with anaqueous solution of sodium hydroxide and extracted with chloroform. Theorganic phase was dried over anhydrous magnesium sulfate and freed fromthe solvent by distillation. The residue was purified by silica gelcolumn chromatography (0 to 3 to 6 to 10 to 20 to 30%methanol/chloroform) to give the title compounds as two fractions(fraction 1:270 mg, fraction 2:260 mg). The fraction 1 refers to that ofa shorter retention time, while the fraction 2 refers to that of alonger retention time.

<fraction 1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.08(s, 1H), 8.04(d, J=6.6 Hz, 1H),6.47(s, 1H), 4.88-4.81(m, 1H), 4.49-4.40(m, 1H), 4.38(s, 2H),3.39-3.31(m, 1H), 3.15-3.10(m, 1H), 2.55(s, 3H), 2.33-2.24(m, 1H),2.01-1.76(m, 6H), 1.70-1.64(m, 3H), 1.64-1.48(m, 3H), 1.28-1.18(m, 1H)

<fraction 2>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.13(s, 1H), 8.04-7.97(m, 1H),6.49(s)+6.47(s)(1H), 4.96-4.80(m, 2H), 4.39(s, 2H), 3.40-3.32(m, 1H),3.24-3.18(m, 1H), 2.83-2.70(m, 1H), 2.48(s, 3H), 1.92-1.71(m, 4H),1.70-1.50(m, 7H), 1.45-1.34(m, 2H)

Example 52

Resolution of diastereomers of fraction 2 of Example 51

The fraction 2 (740 mg) of the Example 51 was subjected to HPLC with achiral cel (Chiralcel OD, a product of Daicel Chemical Industries, Ltd.)and eluted with a mobile phase comprising ethanol, hexane andtriethylamine at a ratio of 10:90:0.5 to give two fractions (fraction2-1:280 mg, fraction 2-2:110 mg). The fraction 2-1 refers to that of ashorter retention time and the fraction 2-2 refers to that of a longerretention time.

<fraction 2-1>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.13(s, 1H), 8.01(d, J=6.8 Hz, 1H),6.49(s, 1H), 4.96-4.88(m, 1H), 4.88-4.78(m, 1H), 4.37(s, 2H),3.32-3.27(m, 1H), 3.17-3.12(m, 1H), 2.80-2.69(m, 1H), 2.44(s, 3H),1.98-1.85(m, 1H), 1.84-1.75(m, 4H), 1.73-1.51(m, 6H), 1.43-1.30(m, 2H)

MS m/z (FAB): 376 (M⁺ +1)

<fraction 2-2>

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.13(s, 1H), 7.99(d, J=6.9 Hz, 1H),6.47(s, 1H), 4.95-4.88(m, 1H), 4.88-4.79(m, 1H), 4.37(s, 2H),3.34-3.28(m, 1H), 3.18-3.12(m, 1H), 2.80-2.69(m, 1H), 2.44(s, 3H),1.95-1.84(m, 1H), 1.85(d, J=2.0 Hz, 3H), 1.80-1.70(m, 1H), 1.71-1.46(m,6H), 1.42-1.35(m, 2H)

MS m/z (FAB): 376 (M⁺ +1)

Example 53

(S)-N-(8-Methyl-8-azabicyclo 3.2.1!oct-2α- or2β-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide hydrochloride##STR71##

The fractions 1 and 2 prepared in the Example 51 and the fractions 2-1and 2-2 prepared in the Example 52 were each treated in a similar mannerto that of the Example 35 to give the title compounds.

<hydrochloride of fraction 1 of Example 51>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 8.02-7.94, 7.93(m+d, J=4.7 Hz, 1H),7.66, 7.62, 7.54, 7.53(s×4, 1H), 6.61, 6.59, 6.58, 6.56(s×4, 1H),6.10-5.90(m, 2H), 5.01-4.91(m, 1H), 4.46-4.27(m, 1H), 4.04-3.96(m, 1H),3.90-3.81(m, 1H), 3.41-3.33(m, 1H), 2.88-2.75(m, 3H), 2.05-1.90(m, 2H),1.85-1.76(m, 3H), 1.70-1.34(m, 8H)

MS m/z (FAB): 876 (M⁺ +1)

<hydrochloride of fraction 2 of Example 51>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 9.90(br.s, 1H), 8.01, 7.99(d×2, J=5.7Hz, 1H), 7.61+7.58(s×2, 1H), 6.60(s, 1H), 6.05(br.s, 2H), 5.08-4.99(m,1H), 4.83-4.71(m, 1H), 3.98-3.91(m, 1H), 3.87-3.81(m, 1H), 3.35-3.30(m,1H), 2.86, 2.78(d×2, J=5.1 Hz, 3H), 2.14-1.87(m, 2H), 1.83, 1.80(d×2,J=1.8 Hz, 3H), 1.74-1.62(m, 4H), 1.61-1.48(m, 4H)

MS m/z (FAB): 376 (M⁺ +1)

<hydrochloride of fraction 2-1 of Example 52>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 9.81(br.s, 1H), 8.01(d, J=5.7 Hz,1H), 7.58(s, 1H), 6.61(s, 1H), 6.04(s, 2H), 5.08-5.00(m 1H),4.81-4.71(m, 1H), 3.98-3.78(m, 2H), 3.32-3.30(m, 1H), 2.78(d, J=5.0 Hz,3H), 2.11-1.87(m, 2H), 1.81(d, J=1.8 Hz, 3H), 1.77-1.62(m, 4H),1.61-1.46(m, 4H)

MS m/z (FAB): 376 (M⁺ +1)

α!_(D) ²³ =-115.2° (C=1.0, MeOH)

<hydrochloride of fraction 2-2 of Example 52>

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 9.76(s, 1H), 7.99(d, J=5.7 Hz, 1H),7.61(s, 1H), 6.60(s, 1H), 6.06(s, 2H), 5.09-5.00(m, 1H), 4.82-4.72(m,1H), 3.98-3.91(m, 1H), 3.89-3.81(m, 1H), 3.35-3.30(m, 1H), 2.86(d, J=5.1Hz, 3H), 2.06-1.85(m, 2H), 1.83(d, J=1.8 Hz, 3H), 1.75-1.63(m, 4H),1.61-1.50(m, 4H)

MS m/z (FAB) 376 (M⁺ +1)

α!_(D) ²³ =-80.3° (C=1.0, MeOH)

Example 54

(S)-N-(1-Azatricyclo 3.3.1.1³,7!dec-10-yl)-4-amino-5-chloro-(1-methyl-2-butynyl)oxybenzamide ##STR72##

The title compound was prepared in a similar manner to that of theExample 43.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 8.09(d, J=5.7 Hz, 1H), 8.04(s, 1H),6.51(s, 1H), 4.99-4.91(m, 1H), 4.54(s, 2H), 4.36-4.30(m, 1H),3.62-3.55(m, 2H), 3.49-3.45(m, 2H), 3.41-3.35 (m, 2H), 2.48-2.42(m, 2H),2.31-2.26(m, 1H), 2.11-2.08(m, 4H), 1.88(d, J=2.0 Hz, 3H), 1.70(d, J=6.4Hz, 3H)

Example 55

(S)-N-(1-Azatricyclo 3.3.1.1³,7!dec-10-yl)-4-amino-5-chloro-(1-methyl-2-butynyl)oxybenzamidehydrochloride ##STR73##

The title compound was prepared in a similar manner to that of theExample 35.

¹ H-NMR (400 MHz, d₆ -DMSO) δ ppm: 10.69(s, 1H), 7.93(d, J=6.0 Hz, 1H),7.54(s, 1H), 6.61(s, 1H), 5.80(br.s, 2H), 5.00-4.92(m, 1H), 4.01-4.04(m,1H), 3.94-3.54(m, 6H), 2.25-2.17(m, 2H), 2.09-1.99(m, 3H), 1.93-1.85(m,2H), 1.83(d, J=1.8 Hz, 3H), 1.59(d, J=6.4 Hz, 3H)

MS m/z (FAB): 388 (M⁺ +1)

We claim:
 1. An aminobenzoic acid derivative represented by thefollowing general formula (I) or a pharmacologically acceptable saltthereof: ##STR74## wherein R¹ represents a group represented by theformula: ##STR75## wherein A and B each represents a group representedby formula --CH₂ --X--CH₂ (wherein X represents O, >N--R⁶ or >CHR⁷(wherein R⁶ represents lower alkyl; and R⁷ represents hydrogen or loweralkoxy)R² represents hydrogen, lower alkyl or arylalkyl; R⁹ representsalkynyl; R¹⁰ represents amino, acylamino or alkylamino; and R¹¹represents halogen.
 2. An aminobenzoic acid derivative represented bythe following general formula (II) or a pharmacologically acceptablesalt thereof: ##STR76## (wherein R¹⁰ represents amino, acylamino oralkylamino; R¹¹ represents halogen; R¹² and R¹³ each represent loweralkyl; a is an integer of 1 to 5; and b is an integer of 0 to 5).
 3. Apharmacological composition comprising a pharmacologically effectiveamount of the compound as defined in claim 1 or a pharmacologicallyacceptable salt thereof, and a pharmacologically acceptable carrier. 4.A method for preventing or therapeutically treating a disease againstwhich serotonin antagonism or an acetylcholine release acceleratingaction is efficacious which comprises administering a pharmacologicallyeffective amount of the compound as defined in claim 1 to a subject whosuffers or will suffer from said disease.
 5. A pharmacologicalcomposition comprising a pharmacologically effective amount of thecompound as defined in claim 2 or a pharmacologically acceptable saltthereof, and a pharmacologically acceptable carrier.
 6. A method forpreventing or therapeutically treating a disease against which serotoninantagonism or an acetylcholine release accelerating action isefficacious which comprises administering a pharmacologically effectiveamount of the compound as defined in claim 2 to a subject who suffers orwill suffer from said disease.